Salmonella spp. are a cause of significant worldwide morbidity and mortality. These organisms primarily cause two clinical manifestations: typhoid fever and gastroenteritis. During oral infection, salmonellae interact with the host innate immune system within the gut and, after passing through the intestinal epithelial barrier, within host cells. A key component of the innate immune system in these locations are antimicrobial peptides (APs): ubiquitous proteins that destroy bacterial membranes. PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are Salmonella spp. two-component regulatory systems (TCSs) that detect host signals and/or activate genes during infection. One signal these systems have been shown to sense in vitro are APs, and this sensing leads to modification of the lipopolysaccharide that covers the bacterial surface. An outcome of these modifications is increased resistance to AP-mediated killing. While much is known in vitro about the signals that activate these TCSs and the phenotypes that result from PhoPQ and PmrAB induction, little is known about the in vivo signals or about the role that PmrAB-mediated LPS modifications play in altering the innate immune response. Thus we will pursue the hypotheses that APs are an in vivo activating signal and that the LPS modifications that protect against AP killing also dampen multiple aspects of the innate immune response. Furthermore, we will investigate the PmrAB TCS and its function in the strict human pathogen Salmonella enterica serovar Typhi, where this important regulatory system has been poorly characterized. These studies will provide a greater understanding of the adaptation of salmonellae to the in vivo environment and shed light on ways to interfere with in vivo induced mechanisms of pathogenesis. PUBLIC HEALTH RELEVANCE: Salmonella spp. are a cause of significant worldwide morbidity and mortality. During infection, the bacterium senses and responds to host derived signals. In sensing this environment, the bacterium modifies its surface to aid survival in the harsh host milieu. Our proposed work will uncover new therapeutic approaches through a better understanding of these important Salmonella sensory mechanisms.